Salpingectomy and the Risk of Ovarian Cancer in Ontario

Key Points Question Is salpingectomy associated with a lower risk of developing ovarian cancer? Findings In this cohort study of 131 516 women in Ontario, there were 31 incident ovarian cancers among 32 879 women (0.09%) who had a salpingectomy compared with 117 incident ovarian cancers among 98 637 women (0.12%) who did not have a pelvic procedure. Meaning These findings suggest no association between salpingectomy and the risk of ovarian cancer among women in the general population; given the rarity of this disease, additional follow-up is needed to reevaluate the potential association in an aging cohort.

A tubal ligation cohort was defined using a similar approach to what was described above. Women were observed from the date of cohort entry to their first tubal ligation in the DAD/SDS databases that occurred in the accrual period. The index date was defined as 180 days post-tubal ligation. Women were excluded based on the criteria listed above, or if they had a history of a hysterectomy or salpingectomy surgery.

General population cohort
We sought to identify a cohort of women that could serve as non-surgery control subjects. To do this we randomly assigned index dates to all subjects in the inclusion cohort. Index dates were randomly assigned based on the distribution of index dates among all eligible women in the salpingectomy cohort. Women were excluded from the non-surgery cohort if they had a history of a salpingectomy or hysterectomy prior to their index date. Women in the surgical cohorts were eligible to serve as non-surgical controls if their randomly assigned index date preceded their surgical date.

Covariates
We collected information on a series of variables which describe demographic information, health services utilization, reproductive history, comorbidities, and indications for surgery (among surgical subjects). Demographic variables include age at index date, calendar year, neighbourhood income quintile, residence location (urban, rural), and years eligible for provincial health coverage. Health services utilization variables include history of core primary care visits, specialist visits, inpatient hospitalizations, and emergency department visits. We used the Ontario Mother-Baby linked dataset (MOMBABY) to measure parity as well as any recent delivery hospitalizations. We identified any history of an ovary surgery (non oophorectomy) or sub-total hysterectomy. The Johns Hopkins ACG System software (version 10) was used to capture aggregate diagnosis groups (ADG) based on health services use in the two years prior to a subject's reference date. The reference date is defined as the date of surgery among surgical patients, and 180 days prior to the randomly assigned index date among non-surgical control subjects. The reference date was used to measure health services use prior to any exposure events. Finally, indications for surgery were captured among subjects that had undergone a tubal ligation, salpingectomy, or hysterectomy. The hospitalization record corresponding to the index surgery was used.

Salpingectomy subjects
Salpingectomy patients were 1:3 matched to women with no gynecologic surgery. Subjects were hard matched on year of index date, age at index date (±2 years), parity, history of tubal ligation, and propensity score. Women that had undergone a salpingectomy alone had different demographic features and surgical indications to women that had undergone a salpingectomy plus hysterectomy. To account for this difference, we ran two separate propensity score models, one for each salpingectomy subgroup (salpingectomy alone, and salpingectomy plus hysterectomy). The propensity score model incorporated income quintile, rurality, years eligible for provincial health coverage, number of primary care visits, history of sub-total hysterectomy, and individual ADGs. Subjects were calliper matched on a value that was 0.2 times the standard deviation of the logit of the propensity score.
We sought to evaluate the association with a surgical comparator group. We performed a second set of matching where salpingectomy patients were 1:1 matched to patients that had undergone a hysterectomy alone. Two separate sets of matches were also performed, one for each salpingectomy subgroup. Propensity score models included variables listed previously as well as variables for surgical indications (abnormal bleeding, endometriosis, fibroids, and pelvic pain).

Tubal ligation subjects
Tubal ligation subjects were 1:3 matched to women with no gynecologic surgery. Tubal ligation subjects were matched using the same methodology and variables described in the salpingectomy cohort, however matched controls could not have a history of tubal ligation.

Primary outcomes
The primary outcome of interest was a diagnosis of incident invasive epithelial ovarian, fallopian tube or peritoneal cancer documented in OCR during the follow-up period. Incident ovarian cancers included any women with ICD 10 codes C56, fallopian tube cancer included ICD 10 codes C57.0 and peritoneal cancer included ICD 10 codes C48.1 and C48.2 (Supplemental Table  1). Matched subjects were followed from their index date to the first of: a primary outcome event, death, end of OHIP eligibility, oophorectomy, or December 31 st , 2021.

Tracer outcomes
Tracer events are predefined outcomes that are expected to have no association with the exposure variable. A significant association with these outcomes may indicate the presence of residual confounding or bias. We selected two cancer-related tracer outcomes that we suspect would not be associated with salpingectomy. We used the OCR to capture incident breast cancer (ICD-10 C50) and incident lung cancer (ICD-10 C34) as tracer events. Subjects were followed using the same approach as in the primary outcomes.

Statistical analysis
Baseline descriptive characteristics of the groups were compared using standardized differences. A standardized difference of less than 0.10 was used to determine comparability between the groups for each covariate of interest. Kaplan-Meier analysis was used to estimate the cumulative incidence of cancer among matched subjects. Crude incident rates of cancer were calculated for each group by dividing the number of outcome events by the total number of person-years in the follow-up period. Cox proportional hazards models were used to estimate the adjusted hazard ratio (HR) and 95% confidence intervals (CI) for each exposure group.

Sensitivity analysis
In a sensitivity analysis we censored women that underwent a gynecologic surgery of interest in the follow-up period which may bias the effect estimates. Specifically, no gynecologic surgery controls and tubal ligation subjects were censored if they underwent a salpingectomy or hysterectomy in the follow-up period while women that had undergone a salpingectomy without a hysterectomy were censored if they had a hysterectomy in the follow-up period.     Aggregate diagnosis groups (cont.) Mean (SD) 6.9 (3.0) 6.9 (3.1) 6.9 (